EP0987021B1 - Slow release compositions containing a zinc compound and vitamin C derivatives - Google Patents

Slow release compositions containing a zinc compound and vitamin C derivatives Download PDF

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Publication number
EP0987021B1
EP0987021B1 EP99307047A EP99307047A EP0987021B1 EP 0987021 B1 EP0987021 B1 EP 0987021B1 EP 99307047 A EP99307047 A EP 99307047A EP 99307047 A EP99307047 A EP 99307047A EP 0987021 B1 EP0987021 B1 EP 0987021B1
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EP
European Patent Office
Prior art keywords
zinc
compound
composition according
ascorbic acid
cupric
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP99307047A
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German (de)
English (en)
French (fr)
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EP0987021A1 (en
Inventor
John C. Godfrey
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Individual
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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/36—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
    • A23G3/364—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G3/368—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A23L33/165—Complexes or chelates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to zinc compositions for oral use and methods of making them. More particularly, this invention relates to compositions containing a combination of a zinc compound (acting as a source of zinc ions) and a source of ascorbic acid (Vitamin C), which when taken orally are palatable and have no undesirable aftertaste. These compositions include, in addition to the zinc compound and the ascorbic acid source, an amino acid, and a base material.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • Zinc therapy is life saving in acrodermatitis enteropathica, a genetic disease caused by an autosomal recessive trait which, although rare, had an extremely high mortality rate until it was discovered in 1973 that chronic administration of oral zinc salts was not only life saving but capable of lifetime control of the disease.
  • Zinc supplementation markedly improves wound healing in zinc-deficient individuals.
  • Zinc deficiency is an important feature in many cases of sickle cell anaemia characterized by growth retardation and hypogonadism, and zinc appears to have a pharmacological anti-sickling effect.
  • Zinc has also been shown to be beneficial in the relief of acute inflammatory conditions associated with rheumatoid arthritis.
  • This study used sugar-based lozenges containing zinc gluconate equivalent to 23 mg of zinc, and glycine, prepared by serial dilution technology to produce a formulation according to U.S. Patent No. 4,684,528 and U.S. Patent No. 4,758,439.
  • Participants in this study who met protocol requirements and who received active lozenges within two calendar days of the onset of cold symptoms and dissolved them in their mouths every 2 hours while awake, as specified in the protocol carried out under a U.S. Investigational New Drug Application, experienced colds that lasted only 58% (mean duration) as long as patients who received a placebo. Patients in this study who received the active medication also experienced significant reductions of symptom severity and duration as compared to those who received the placebo.
  • zinc gluconate by itself has a very bad taste. This may be overcome by formulations containing an excess of glycine or certain other selected amino acids making the material palatable enough to be taken with the frequency necessary to suppress symptoms of the common cold.
  • Vitamin C ascorbic acid
  • Vitamin C is established as an important nutrient.
  • a combination of a zinc supplement with Vitamin C in a single dose lozenge, or similar type oral dosage form is desirable.
  • EP-A-0 842 664 discloses a composition for oral use including a zinc compound, an amino acid compound, a copper compound and a base material; among the disclosed zinc compounds is zinc ascorbate.
  • US-A-5 626 883 discloses various vitamin C supplements which include compositions containing at least one amino acid, ascorbic acid, magnesium ascorbate, ascorbyl palmitate and zinc ascorbate.
  • US-A-5 759 559 discloses an oral supplement containing zinc and ascorbic acid which is used in conjunction with a topical spray in the treatment of acne.
  • the problem underlying the present invention is to provide a combination of zinc and ascorbic acid (Vitamin C) for oral consumption, which avoids the unpalatability and bad aftertaste which have characterised prior attempts to provide a product for oral consumption including zinc and ascorbic acid.
  • a slow release composition comprising a zinc salt or salts (as a source of zinc ions), certain sources of ascorbic acid, certain amino acids, and a base material (such as candy or syrup) are characterised by selecting as the ascorbic acid source, at least one of ascorbyl esters, magnesium salts thereof and magnesium ascorbate.
  • Such compositions may be formulated to be very pleasant to the taste and to leave no undesirable aftertaste.
  • a minor molecular proportion of a copper salt may be included to eliminate potential adverse effects of excess zinc in the body.
  • magnesium L-ascorbate i.e., the magnesium salt of L-ascorbic acid
  • L-ascorbyl palmitate and its magnesium salt are each individually suitable for combination with zinc salts in oral dosage compositions while avoiding the association of zinc ions with ascorbic acid and, thus, avoiding the resulting undesirable flavour therefrom.
  • the magnesium salt of L-ascorbic acid is commercially available from SIGMA.
  • L-ascorbyl palmitate is commercially available from Chemical Dynamics Corp.
  • Amino acids useful in the present invention are monocarboxylic amino acids including glycine, L-alanine, D,L-alanine, L-2-aminobutyric acid, D,L-2-aminobutyric acid, L-valine, D,L-valine, L-isovaline, D,L-isovaline, L-leucine, D,L-leucine, D-isoleucine, D,L-isoleucine, L-lysine, and D,L-lysine.
  • Zinc compounds useful in combination with the amino acid and the ascorbic acid source can be in any of the forms commonly used, such as the sulfate, carbonate, chloride, acetate, gluconate, citrate, aspartate, picolinate, orotate, and transferrin salts, as well as zinc oxide and complexes of divalent zinc with the amino acids. Mixtures of zinc salts may also be used.
  • the base material which can be used as a carrier for the zinc compound, amino acid, and source of ascorbic acid can be a sweetening agent such as a soft or hard candy base.
  • a syrup such as corn syrup, or a gum material such as chewing gum may be used.
  • Any form which permits the oral intake of the zinc/ascorbic acid combination and particularly where the composition is retained in the mouth for a substantial period of time to permit prolonged contact in the mouth with the zinc to provide a slow release of zinc into the mouth may be used.
  • the base material is a hard or soft candy base optionally containing a flavouring agent such as a fruit flavour concentrate or a syrup such as a natural or artificially sweetened syrup.
  • composition of the present invention may also optionally include a minor proportion relative to zinc (about 0.01 to 0.1 molar equivalents) of a copper salt such as the sulfate, chloride, acetate, gluconate, ascorbate, citrate, aspartate, carbonate, picolinate, orotate and transferrin salts, as well as cupric oxide and complexes of divalent copper with amino acids.
  • a copper salt such as the sulfate, chloride, acetate, gluconate, ascorbate, citrate, aspartate, carbonate, picolinate, orotate and transferrin salts, as well as cupric oxide and complexes of divalent copper with amino acids.
  • Suitable ratio ranges for use in the composition of the present invention include approximately 2 to 20 moles of amino acid(s) per mole of zinc ions (i.e., zinc compound), and approximately 0.01 to 0.10 mole of cupric ions per mole of zinc ions.
  • the ascorbic acid or equivalent is present based on the source of ascorbic acid in an amount of about 30-300 mg per 4.5 g of lozenge. It is noted that in view of the ascorbate sources, it is technically difficult to make lozenges with much more than 120 mg of ascorbic acid (or equivalent) per 4.5 g of lozenge.
  • the lozenges of the present invention most preferably contain approximately 0.2 mmol zinc in the form of zinc gluconate, approximately 0.35 mmol ascorbic acid in the form of magnesium L-ascorbate or L-ascorbyl palmitate, approximately 2.0 mmol glycine, and a hard candy base of approximately 4.5 g. These amounts may also be scaled up to produce a larger or a smaller lozenge.
  • magnesium ascorbate is C 12 H 14 O 12 Mg with a molecular weight of 374.53.
  • the ascorbic acid salt as commercially available, however, is 95% active.
  • the ascorbic acid anion has a mol. wt. of 175.11 and it is desired, in the specific examples set forth and generally, to place an equivalent of 60 mg of pure ascorbic acid in one 4.5 g lozenge.
  • each 4.5 g lozenge will contain 68 mg of magnesium ascorbate (95%).
  • Zinc will be present as 104 mg of zinc gluconate trihydrate in the 4.5 g lozenge of the examples.
  • glycine 153 mg (i.e., 10 molar equivalents as compared to the zinc ions) of glycine will be present in each 4.5 g lozenge of the examples.
  • the hard candy base will make up 4.175 g of the 4.5 g lozenge.
  • an unflavoured hard candy base was first prepared by the following procedure: a mixture of 360 g sucrose, 40 g fructose, 160 ml light KARO® corn syrup, and 160 ml water in a Teflon-lined 1.9 litre aluminum pan was brought to a boil while stirring until the temperature of the mixture reached 100°C. Heating was continued without stirring until the temperature reached 149°C. The mixture was then poured into a lightly lubricated (e.g., with a cooking spray such as PAM®) aluminum pan, cooled to room temperature, and fractured into smaller pieces. The pieces were stored at room temperature in a sealed container.
  • a lightly lubricated e.g., with a cooking spray such as PAM®
  • a zinc gluconate glycine concentrate was prepared.
  • a mixture of 61.2 g glycine and 41.6 g zinc gluconate trihydrate was ground together in a grinder to a very fine zinc gluconate/glycine (ZGG) powder.
  • the resulting lozenges were found to have a pleasant flavour, strong zinc ion astringency, and a slight grittiness. No trace of bad taste due to zinc ion-ascorbic acid interaction was detected nor was there any bad aftertaste. No change was detected upon reevaluation after 15 days, and after 5 months storage at room temperature in a sealed container. Thus, it is clear that no exchange of Zn 2+ for Mg 2+ occurred in this formulation, for if such exchange had occurred, the well-established foul taste of zinc ascorbate would have been readily detectable.
  • L-ascorbyl palmitate as used herein is as commercially available from Chemical Dynamics Corp., Product No. 08-380-000.
  • L-ascorbyl palmitate has a molecular weight of 414.53.
  • Ascorbate ion has a molecular weight of 175.11.
  • one lozenge of the example will include 158 mg of 90% L-ascorbyl palmitate, 104 mg zinc gluconate trihydrate, 153 mg glycine, and 4.085 g of HCB.
  • This material was transferred to a lightly lubricated or greased aluminum pan, spread out to form a 150mm disc or "cookie", and scored into square lozenges as it cooled.
  • the disc was broken into approximately 4 g to 5 g lozenges.
  • the resultant lozenges were found to have a pleasant taste, be notably astringent, and have no aftertaste. There was a slight "waxy" feel in the mouth, especially on the occlusal surfaces of the teeth, due to the palmitic acid moiety of the LAP. The taste noticeably improved after 2 days storage at room temperature and was entirely stable for at least five months. Thus, it is clear that no hydrolysis of the palmitate ester occurred under the conditions of this preparation, for if such hydrolysis had occurred, there would have been some metathesis to zinc ascorbate, readily detectable by its foul taste.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Compositions Of Oxide Ceramics (AREA)
  • Electroplating And Plating Baths Therefor (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP99307047A 1998-09-03 1999-09-03 Slow release compositions containing a zinc compound and vitamin C derivatives Expired - Lifetime EP0987021B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US145975 1993-11-01
US09/145,975 US6316008B1 (en) 1998-09-03 1998-09-03 Combination of zinc ions and vitamin C and method of making

Publications (2)

Publication Number Publication Date
EP0987021A1 EP0987021A1 (en) 2000-03-22
EP0987021B1 true EP0987021B1 (en) 2003-04-09

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EP99307047A Expired - Lifetime EP0987021B1 (en) 1998-09-03 1999-09-03 Slow release compositions containing a zinc compound and vitamin C derivatives

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US (1) US6316008B1 (xx)
EP (1) EP0987021B1 (xx)
JP (1) JP3875811B2 (xx)
AT (1) ATE236620T1 (xx)
AU (1) AU755724B2 (xx)
BR (1) BR9904036A (xx)
CA (1) CA2281054C (xx)
DE (1) DE69906651T2 (xx)
IL (1) IL131541A0 (xx)
ZA (1) ZA994998B (xx)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003510363A (ja) 1999-10-04 2003-03-18 カーター、ジョン 医薬組成物及びその使用法
GB2374008B (en) * 2001-04-04 2005-03-16 John Carter Pharmaceutical compositions comprising copper and zinc
US20040151771A1 (en) * 2003-02-04 2004-08-05 Gin Jerry B. Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth
WO2004098571A1 (en) * 2003-04-30 2004-11-18 Zicam, Llc Cold remedy composition comprising zinc salts
US20070092552A1 (en) * 2003-04-30 2007-04-26 Tim Clarot Chewable lozenge cold remedy composition and method for making same
JP4929628B2 (ja) * 2004-07-08 2012-05-09 大正製薬株式会社 亜鉛含有内服液剤
WO2006135445A2 (en) * 2004-11-03 2006-12-21 Albion Laboratories, Inc. Antimicrobial chelates
US20090081294A1 (en) * 2007-09-26 2009-03-26 Gin Jerry B Sustained release dosage form for lubricating an oral cavity
US20090081291A1 (en) * 2007-09-26 2009-03-26 Gin Jerry B Sustained Release Dosage Forms For Delivery of Agents to an Oral Cavity of a User
WO2010053833A1 (en) 2008-11-04 2010-05-14 Vymedic, Llc Antiviral supplement formulations
US8247435B2 (en) * 2009-02-19 2012-08-21 Thornthwaite Jerry T Formulations for treating human and animal diseases
EP2283805A1 (en) 2009-07-28 2011-02-16 Sirvis BV Compositions comprising a zinc containing compound dissolved in a hydrophobic phase
US20110028412A1 (en) * 2009-08-03 2011-02-03 Cappellos, Inc. Herbal enhanced analgesic formulations
NZ744260A (en) * 2016-01-15 2020-07-31 Novex Science Pte Ltd Stable and palatable composition of vitamin c and zinc lozenge tablets
CN107913294A (zh) * 2017-10-31 2018-04-17 安徽鸿泰食品有限公司 一种孕妇补锌营养液
CA3150164C (en) * 2020-07-17 2022-10-04 Jost Chemical Co. Divalent metal ascorbate glycinate co-salt

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63141921A (ja) 1986-12-04 1988-06-14 Kao Corp 口腔用組成物
WO1991011117A2 (en) 1990-02-05 1991-08-08 Board Of Regents, The University Of Texas System Dietary supplements comprising vitamins and minerals
US5326569A (en) * 1992-12-23 1994-07-05 Abbott Laboratories Medical foods for the nutritional support of child/adult metabolic diseases
US5626883A (en) 1994-04-15 1997-05-06 Metagenics, Inc. Ascorbic acid compositions providing enhanced human immune system activity
US5897891A (en) * 1996-11-18 1999-04-27 Godfrey; John C. Flavorful zinc compositions for oral use incorporating copper
US5759559A (en) 1997-05-05 1998-06-02 Fitzjarrell; Edwin A. Method and composition for treating acne

Also Published As

Publication number Publication date
DE69906651T2 (de) 2003-12-18
ATE236620T1 (de) 2003-04-15
JP2000086522A (ja) 2000-03-28
ZA994998B (en) 2000-02-18
DE69906651D1 (de) 2003-05-15
CA2281054C (en) 2002-11-19
AU755724B2 (en) 2002-12-19
BR9904036A (pt) 2000-09-26
IL131541A0 (en) 2001-01-28
EP0987021A1 (en) 2000-03-22
US6316008B1 (en) 2001-11-13
AU4734999A (en) 2000-03-16
CA2281054A1 (en) 2000-03-03
JP3875811B2 (ja) 2007-01-31

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